Colloidal metallic bismuth and method of preparing, packaging, and using it



s sle UNITED STATES COLLOIDAL METALLIC BISMUI'H AND METHOD OF PBEPABING, PACKAGING,

AND USING IT;

-Walter G. Christiansen, Glen Ridge, N. I., Alfred" E. Jurist, Brooklyn,and Eugene Moncas, Far

Bockaway, N. Y., assignors to E. B. Squibb & Sons, Brooklyn, N. Y., acorporation of New york No Drawing. Application October 10, 1931,

Serial No. 568,198

Claims. (Cl. urn-cs)v This invention relates to colloidal metallicbismuth and compositions containing it adapted for therapeutic uses, andto methods of preparing these materials.

5 The invention is of particular value in aflording a product which maybe employed for devitalizing, that is destroying, inhibiting the growthof, or rendering harmless luetic spirochetes. The product andpreparations including it may be employed, however, for othertherapeutic purposes.

Colloidal metallic bismuth has been prepared- 35 -It is the-object oithe invention to provide a simple and eflective method of preparingcolloidal metallic bismuth, and particularly a solution of colloidalmetallic bismuth which can be utilized without initial drying, theproduct being substantially free from contaminating materials.)

Another object of the invention is to afford a product which may berecovered in dry, granular condition, capable of being dissolved toafi'ord suitable solutions for therapeutic use.

Other objects and advantages of the invention will be better understoodby reference to the following specification.

We have discovered that colloidal metallic bismuth can be prepared in adesirable form by 4Q reducing a solution of a bismuth compoundcontaining a suitable sugar. Several sugars have been found to beeffective for the purpose of the invention, including mannite, sorbitoland levulose. The colloidal bismuth which is sepa rated by evaporationfrom such a solution is a dry granular material which is readily solublein water. The absence of glycerin avoids stickiness and permits thecompletion of the reaction and the separation of a satisfactory product.

It is necessary to protect the solution from atmospheric oxidation andeffect of carbon dioxide during the reduction, and for this purpose weprefer to cover the solution with a layer of a suitable material havingcharacteristics which.

permit substantially complete removal thereof during the evaporationsubsequent to reduction. Various materials may be used. Thecharacteristics of a suitable oxygen-excluding liquid are:

1. Water insoluble.

2. Specific gravity: less than i.

3. Chemically inert. This does not mean that the substance is incapableof undergoing chemical reactions but means that under the conditions ofuse it does not undergo chemical change.

4. Volatility.

(a) The liquid may have a boiling point less than 100 C. at atmosphericpressure.

(12) It may have a boiling point slightly above 100 C. at atmosphericpressure but be'readily volatile in the steam which is formed during theevaporation of the dialyzed reaction The -vaporizable liquid of theaccompanying claims is aliquid having these'characteristics.

The most satisfactory of these materials is ben- -zol which is readilyremoved from the solution preparing a water solution of mannite,sorbitol or levulose (fructose) and bismuth nitrate pentahydrate andadding it to a solution of a protectingvcolloid, such as acacia, inproper concentration. The solutionis protected then by .85 the layer ofoxygen and carbon dioxide-excluding material such as benzol. Thereducing, agent, preferably asodium hydrosulphite solp tion stabilizedby the addition of a small amount of concentrated ammonia is addedslowly while the mixture is thoroughly stirred.

The reduction to the free metal proceeds rapidly, and when'completed thesolution is' distributed in dialyzing bags and dialyzed for aboutseventy-two hours with running water preferably freed from oxygen andcarbon dioxide by previous boiling and cooling, at room temperature. Theliquid in each bag must be protected with a layer of theoxygen-excluding material. When the dialysis is completed, as 1 much aspossible of the oxygen-excluding material is removed by means of aseparatory funnel. The solution is then concentrated to about one-tenthof its original volume in 'a steam jacketed vacuum still. Any excess ofthe oxygenexcluding material is removed during the concentration.

The resulting solution can be packaged in suitable oxygen and carbondioxide-excluding ampoules of glass or other suitable material for nowithout further'treatment. Alternatively the 'permits the preparation ofsatisfactory thera peutic products. The solution, whether obtained 7contaminating matcrialfsuch as glycerin and colloidal metallic bismuthmay be separated in dry-form and then redissolved in water before it isaackzaiged. The separation'can be accom-v plished'either by evaporatingto dryness under vacuum orby precipitating by adding alcohol,

' filtering the, precipitate and drying it under of of properconcentration may be packaged inv air-excluding 'amooules of glass orother; suitable material.

'The met-hodas describedatfords a simple and efiectiveprocedure wherebycolloidal metallic bismuth may be obtained in a' form which directly byevaporation or by evaporation to dry ness and subsequent solution'yofthe dry colloidal metallic bismuth, is substantially free frompetrolatuin, The product. is. therefore, more readily usable thereforemore desirable forv fl excluding material to: avoidpossible oxidationits intended purpose. 4

As an example-of the invention the following serve to illustratc'theprocedureiwe prepare 440 cc. of a 13% mannite and 14% bis- :nuth nitratepentahvdrate solution and add it then slowly add to the mixture withthorough to 7500' ccyof: a 0.9% acacia solution. vThe resulting mixtureis protected'by a layer of an oxygen-excluding material such as .benzol.We

stirring 1500 cc. of a clarified 2% sodium hydrasulphitc solution vvhichhas been stabilized by the addition of 10 cc. of concentrated ammonia.The stirring is continued until the reduction to the free colloidalmetallic bismuth is completed.

The bismuth-acacia ratio needs to be very close to that which exists inthe above mixture. Thisisnecessarybecausetheacaciaistheprotectivecolloid for the bismuth and if the bismuth-acacia ratio varies to anygreat extent.

add more mannite than is necessary. Similar proportions of sorbitol orlevulose (fructose) can be used with satisfactory results. Lactose,dextrose and sucrose are not equivalent sugars and cannot be usedsuccessfully in the procedure described The total volume is close to8000 cc. This volume should not be decreased because as theconcentration of a reaction mixture increases during the production of acolloid the possibility of obtaining large particles is increased. Thevolume of water can be increased as much as one desires. However, theuse of 16,000 instead oi 8,006 cc. does not seem to improve the qualityof the colloidwhich we have prepared and it is impractical vto uselarger volumes than are The quantity of hydrosulphite is based on thereducing power of the latter and is just sumcient to obtain the desiredreduction. Onecould use more but there-is no advantage in doing so andthe amount of materialwhich would have to be removed upon dialysis wouldbe increased. I We use the sodium hydrosulphite in 2% aqueous solution-,A more concentrated solution, example 10 could be used but it isnecessary .to add the hydrosulphite gradually so as'to avoid large localconcentrations.

The gradual I for Y ried, but. it is undesirable to use more ammonia 1 1than is necessary because it is undesirable to increase the alkalinity,of, the reduction mixture;

the ammonia which we use is probably all:

neutralized withsulphites from hydrosulphlte l before injury to thecolloid canv occur.

' The solution, still protected by the oxygen-v vexcluding layer, isthen distributed to the dialyzing bags ,and'is ,dialyzed for aboutseventy-two hours with running water at room temperaturdm Each bagshould have ya layer of the oxygenof the product. Alter dialysis iscompleted, the oxygen-excluding material is separated as com pletely; aspossible in a separatory funnel. The

solution is then transferred to a steam jacketed vacuum still andconcentrated to aboutv onetenthof its original volume. The excess of theoxygen-excluding material is removed with the steam evolved during theconcentration.

"The resulting 10% solution or a vsolution seished under vacuum overphosphorous pentoxidc Alternatively the colloidal metallic bismuth canbcprecipitated from the. 10% solution by adding an excess of ethyl alcoholthereto. This aflords a more expeditious procedure, since theprecipitate may be separated readily from the solution by filtering andthen dried under vacuum at about 25 C. over phosphorous vpen-- toxide. vThe dry product in the form of a finely divlded grayish black solid canbe redissolved in water to produce solutions of the desiredconcentration for immediate use or may be packaged in oxygen-excludingampoules and thus preserved for future use.

The procedure as' described produces'a uniform colloid in which theparticle size is small. The solution is free from any second liquidphase such as organic material of the liquid petrolatum type and thecolloidal solution is stable. .Ampouled solution has been kept in thelaboratory for over one year without evidence of deterioration. Thebiological work has also demonstrated that an excellent product from thestandpoint of colloidal properties is obtained.

The solution of colloidal metallic bismuth may v details-oi proportionsand oi the terials new con repisceeimutn mom. melmite, 'tifnQa ,1 i.

excluding mo vt peutic results.

emoed a :1 Although the example illustrates the best known procedure forthe annexation o! the product, various changes be made in. the

usual ployed. Thus, bismuth chloride or uth tarplace Acacia, be y other,w nitrogenous, protecting colloids. tions stcted are those t ees, butwide tion is 5 culoriy, an excess of any oi the ms is not sen;-

erelly 1w but it h nomic. The invention is not, therefore, limited tosuch details but comprehends a pure including the use of Til-:11: teor'its equivalents in the initial solution and the employment ofoxygensuch as henzol end the equivalents therefor which x 1-1-1 t theremoval of such materials d the evaporation of the solution afterreduction of the colic xne= tellic bismuth. The invention crow.- 9Rhends the w trsted solution oi colloidal metallic bismuth; free I 11such as glycerin, petrolatum and other impurities, and a finely dividedsolid product co oi colloidal; metallic bismuth likewise ireo iromconting materials. and packaged anaerobically to ensure the maintenanceof such solotions in condition to oilord the desired then- The termmannite in the nanying claims includes the equivalent aorbitol andlevulose (ti-dome). The term incrt" is used in the eccomiclaims to applyto sub! stances which, under the condi o! use, do not undergo chemicalchange.

Various cos may he therefore. without departing from the invention orsacrifioing any of the advantages We claim:

l. The methodof. Preparing metallic I1 19 a bismuth in cwatcrsoiutioncontniningmsnniteondeprotcctin: colloid under a layer of i an inert,bio, hie, oxygent'he solution and m the oxyeencolloidal metallic em I ..mgme5 layer 0 hle, en-, mlution, evapothe con-exclud ve we ing liquid.precipitating the colloidal metallic uth, and separating and theprecipitote.

3. The thod oi proper-inc colloidal metallic bismuth which com 'ucing o,bismuth water solution con mancompound in e nite its a colloid under alayer of en wetcrble, van: le. oxygenei'zcl m: liquid, solution, eyepo-I rating to we the omen-exclud- 4 lug-liquid, senor-still: and thecolloidal lilo metallic bismuth and l the nth to produce a therapeuticsolution.

I 4. The method of preparing colloidal metallic bismuth which reducing abismuth compound in a water solution containing man- 105 nite anda'protcotinzcolloid under a layer or benzol, dialyzinz the solution andevaporating- 5. The method'o! preparing colloidal metallic bismuth whichcomprises reducing a bismuthllil compound in a water solution containingmannite and at protecting colloid under a layer of bcnzol. the solution,evaporating to remove water and henzol, precipitating the colloidalmetallic bismuth, and separating and dry- 115 in: the brecipitate;

' WALTER G.

EUGENE HONESS. ALFRED E. JURIST.

